bims-pideca 2025-07-06 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2025–07–06
thirteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

A live-cell biosensor of in vivo receptor tyrosine kinase activity reveals feedback regulation of a developmental gradient.
Interconnections of insulin/IGF-1 signaling and autophagy abnormalities in Alzheimer's disease.
Clinicogenomic landscape and function of PIK3CA , AKT1 , and PTEN mutations in breast cancer.
Akt isoform specificity drives intrinsic immune regulation during HSV-1 infection.
Elucidating PTEN conformational dynamics and phosphatase regulation via integrative modeling and mutation prediction.
Activating PIK3CA mutations in adipose-derived stem cells drive mutant-like phenotypes of wild-type cells in macrodactyly.
Multiple Genomic Technologies Validate Rare Novel Variant and Direct Medical Care in Vascular Anomalies.
Force of change: How biomechanical cues drive endothelial plasticity and morphogenesis.
Molecular insight on the role of the phosphoinositide PIP3 in regulating the protein kinases Akt, PDK1, and BTK.
AKT/mTOR as a targetable hub to overcome multimodal resistance to EGFR inhibitors in oesophageal squamous cell carcinoma.
Generation of mature epicardium derived from human-induced pluripotent stem cells via inhibition of mTOR signaling.
The Somatic Mosaicism across Human Tissues Network.
PI3Kγ signaling controls trafficking of CD8+ T cells between lymphoid and non-lymphoid organs and drives hypertension in a murine model.

Cell Rep. 2025 Jun 27. pii: S2211-1247(25)00701-6. [Epub ahead of print]44(7): 115930

A live-cell biosensor of in vivo receptor tyrosine kinase activity reveals feedback regulation of a developmental gradient.

Emily K Ho, Rebecca P Kim-Yip, Alison G Simpkins, Payam E Farahani, Harrison R Oatman, Eszter Posfai, Stanislav Y Shvartsman, Jared E Toettcher.

  A lack of tools for detecting receptor activity in vivo has limited our ability to fully explore receptor-level control of developmental patterning. Here, we extend phospho-tyrosine tag (pYtag) biosensors to visualize endogenous receptor tyrosine kinase (RTK) activity in Drosophila. We build biosensors for three RTKs that function across developmental stages and tissues. By characterizing Torso::pYtag during embryonic terminal patterning, we find that Torso activity differs from downstream extracellular signal-regulated kinase (ERK) activity in two surprising ways: Torso activity is narrowly restricted to the poles but produces a broader gradient of ERK and decreases over developmental time, while ERK activity is sustained, an effect mediated by ERK pathway-dependent negative feedback. Our results suggest that a narrow domain of Torso activity, tuned in amplitude by negative feedback, locally activates signaling effectors, which diffuse through the syncytial embryo to form the ERK gradient. Altogether, the results of this work highlight the usefulness of pYtags for investigating receptor-level regulation of developmental patterning.

Keywords:  CP: Cell biology; CP: Developmental biology; Drosophila development; ERK signaling; biosensor; receptor tyrosine kinases

DOI:  https://doi.org/10.1016/j.celrep.2025.115930
Alzheimers Dement. 2025 Jul;21(7): e70099

Interconnections of insulin/IGF-1 signaling and autophagy abnormalities in Alzheimer's disease.

Wang Liao, Jinfeng Xuan, Woo-In Ryu, Mariana K Bormann, Yoon Lee, Haley Dion, Elizabeth Evangelista, Ruiyi Li, Lucas Trambaiolli, Jun Liu, Arthur J Siegel, Brent P Forester, Bruce M Cohen, Kai-Christian Sonntag.

   INTRODUCTION: Impaired insulin (INS) and insulin-like growth factor 1 (IGF-1) signaling are features of both brain aging and late-onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause-and-effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood.
METHODS: We investigated INS/IGF-1 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals.
RESULTS: Compared to control old-age cells, protein levels in the INS/IGF-1 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS/IGF-1/AKT/FOXO1 or mTOR axes and associated endo- and autophagic processes were largely intact in old-age but disrupted in LOAD fibroblasts.
DISCUSSION: Our results suggest that reduced AKT activation, in the context of altered INS/IGF-1 signaling, and connected alterations of endocytosis and autophagy are features of LOAD pathology but not aging, per se.
HIGHLIGHTS: Levels of insulin/insulin-like growth factor 1 (INS/IGF-1) factors in late-onset Alzheimer's disease (LOAD) cells are higher than in healthy old controls. AKT activation by INS/IGF-1 signaling is specifically diminished in LOAD cells. INS/IGF-1/AKT/forkhead box protein O1/mechanistic target of rapamycin kinase related endocytosis/autophagy are disrupted in LOAD cells. Intracellular endocytic/autophagic structure distribution is altered in LOAD cells. INS/IGF-1 reverses endocytic/autophagic processes in LOAD versus old control cells.

Keywords:  AKT; autophagy; endocytosis; forkhead box protein O1; insulin; insulin‐like growth factor 1; late‐onset Alzheimer's disease; mechanistic target of rapamycin kinase; skin fibroblasts; starvation

DOI:  https://doi.org/10.1002/alz.70099
medRxiv. 2025 Jun 18. pii: 2025.06.18.25329632. [Epub ahead of print]

Clinicogenomic landscape and function of PIK3CA , AKT1 , and PTEN mutations in breast cancer.

Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa Schrock, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan.

Purpose: To comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional implications in AKT-driven breast cancer.
Experimental Design: Comprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne ® CDx or FoundationOne ® . We examined the genomic landscape of PIK3CA , PTEN , and AKT1 alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical PTEN variants.
Results: There were 29,157 total variants across PIK3CA, AKT1, and PTEN , including pathogenic variants and VUS. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%), then AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA -altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while AKT1 and PTEN alterations were balanced across ancestries. PIK3CA , AKT1 , and PTEN pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense PTEN mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function.
Conclusions: Here we present the landscape of PIK3CA , AKT1 , and PTEN alterations in the largest clinical cohort examined to date. The functional implications of lesser-known variants in each gene warrant further investigation by tools such as deep mutational scanning.

DOI: https://doi.org/10.1101/2025.06.18.25329632
Proc Natl Acad Sci U S A. 2025 Jul 08. 122(27): e2504962122

Akt isoform specificity drives intrinsic immune regulation during HSV-1 infection.

Rahul K Suryawanshi, Chandrashekhar D Patil, Hemant Borase, Deepak Shukla.

  Akt isoforms are generally considered functionally redundant, contributing to total Akt activity. However, during HSV-1 infection, Akt1 and Akt2 knockout animals exhibited distinct antiviral responses. Unexpectedly, in the absence of Akt1, Akt2 played a unique role in regulating cytokine production and inactivating proapoptotic transcription factor FoxO3a, a mechanism not shared by Akt1. These findings provide the clearest in vivo evidence yet that Akt isoforms are not functionally redundant, revealing distinct immune-regulatory roles for each isoform and suggesting a broader principle for fine-tuning immunity and cell death across diverse pathological settings.

Keywords:  Akt isoforms; HSV-1; cell death; immunity; survival

DOI:  https://doi.org/10.1073/pnas.2504962122
Structure. 2025 Jun 30. pii: S0969-2126(25)00218-7. [Epub ahead of print]

Elucidating PTEN conformational dynamics and phosphatase regulation via integrative modeling and mutation prediction.

Jennifer Erin Dawson, Iris Nira Smith, Ann Marie Tushar, Charis Eng.

  PTEN (Phosphatase and TENsin homolog deleted on chromosome ten) is a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN is a dual-specificity phosphatase that negatively regulates the PI3K/AKT/mTOR signaling pathway at the plasma membrane (PM). Its functional regulation and cellular localization are known to be conformationally driven. Access to the PM is phosphoregulated by open and closed PTEN forms. However, clarifying the underlying structural mechanisms is still an open avenue of research. Here, we apply an integrative structural modeling approach, combining coarse-grained and all-atom molecular dynamics with experimental crosslinking mass spectrometry. Conformational exchange between an "eased" form and a "strained" form brings the protein's phosphatase and C2 domains closer together, blocking the catalytic site, and affecting the loops involved in PM binding. Our full-length PTEN models, AlphaMissense, and RaSP were used to better predict the consequences of PTEN mutations.

Keywords:  AlphaMissense; PTEN; RaSP stability prediction; XL-MS; clinical mutation; conformational change; crosslinking mass spectrometry; integrative structural modeling; molecular dynamics; molecular modeling

DOI:  https://doi.org/10.1016/j.str.2025.06.002
Cell Death Dis. 2025 Jul 01. 16(1): 477

Activating PIK3CA mutations in adipose-derived stem cells drive mutant-like phenotypes of wild-type cells in macrodactyly.

Xiao Zhang, Yating Yin, Zhibo Wang, Yongkang Jiang, Aiping Yu, Xinyi Dai, Xiaoli Wang, Xuesong Guo, Hailei Mao, Bin Wang.

Macrodactyly is a congenital overgrowth disorder characterized by pathological adipose proliferation due to PIK3CA mutations in adipose-derived stem cells (ADSCs). Due to the somatic mosaicism, the affected tissues comprise a mixture of mutant and wild-type cells. However, how PIK3CA mutated ADSCs influence adjacent wild-type cells in macrodactyly remains poorly understood. In this study, we utilized coculture systems to investigate the effects of macrodactylous adipose-derived stem cells (Mac-ADSCs) on normal ADSCs, fibroblasts (FBs), and vascular endothelial cells (VECs). Our study demonstrated that activating PIK3CA mutations in Mac-ADSCs promotes the proliferation, migration, invasion, adipogenesis, and angiogenesis of wild-type ADSCs, FBs and VECs. Furthermore, using RNA sequencing and cytokine arrays, we revealed that these effects are primarily mediated by various secreted paracrine cytokines. These findings demonstrated that activating PIK3CA mutation alters the paracrine characteristics of Mac-ADSCs and reshapes the microenvironment of macrodactyly, driving adjacent wild-type cells to exhibit mutant-like phenotypes. Targeting PIK3CA with BYL-719 could influence the progression of macrodactyly by inhibiting the paracrine signaling of Mac-ADSCs.

DOI: https://doi.org/10.1038/s41419-025-07795-7
Am J Med Genet A. 2025 Jul 04. e64126

Multiple Genomic Technologies Validate Rare Novel Variant and Direct Medical Care in Vascular Anomalies.

Luciana Daniela Garlisi Torales, Kristina Woodis, Allison Britt, Lea F Surrey, Abhay Srinivasan, Arupa Ganguly, Maria Limmina, Dong Li, Suzanne P MacFarland, Denise M Adams, Sarah E Sheppard.

  Some vascular anomalies, such as hamartomas associated with PTEN hamartoma tumor syndrome (PHTS) and fibroadipose vascular anomaly (FAVA, often due to PI3KCA variants), share similar clinical, radiological, and histopathological presentations that challenge clinicians to provide an accurate diagnosis. Genetic testing can help clinicians differentiate these two vascular anomalies to provide proper treatment for patients. An 11-year-old female with macrocephaly presented with a painful lesion in her right ankle and was initially diagnosed with FAVA and treated with sirolimus. Initial genetic testing from a biopsy sample was negative. Subsequently, however, repeat clinical genetic testing and research deep exome sequencing from a second tissue biopsy sample identified a mosaic variant in PTEN (NM_00314.7) c.683delA p.Asn228Ilefs*28 with a variant allele fraction (VAF) of 2.0%-2.1%, ultimately changing the diagnosis from FAVA to a PTEN hamartoma. To evaluate the germline status of this patient, PTEN sequencing and deletion duplication testing was sent from saliva and identified a different variant in PTEN (NM_000314.4) c.202_209+18delins27, estimated to be 20%-30% VAF. Sanger sequencing validated this novel variant as germline, leading to cancer screening in the patient. This case exemplifies the need for genetic reevaluation as sequencing technology continues to update rapidly, repeat sampling in cases of suspected mosaicism, the two-hit hypothesis in the development of vascular malformations, and emphasizes the importance of genetic diagnosis in vascular malformations, especially in this case which led to the identification of a cancer predisposition syndrome.

Keywords:  PTEN hamartoma; fibroadipose vascular anomaly (FAVA); sirolimus; somatic mosaicism; vascular malformation

DOI:  https://doi.org/10.1002/ajmg.a.64126
Semin Cell Dev Biol. 2025 Jul 02. pii: S1084-9521(25)00033-3. [Epub ahead of print] 103623

Force of change: How biomechanical cues drive endothelial plasticity and morphogenesis.

Dorothee Bornhorst, Newsha Mortazavi, Felix Gunawan.

  Endothelial cells (ECs), which line the inner surface of blood vessels, continuously respond to biomechanical forces from blood flow, extracellular matrix, and intracellular tension. Recent advances have highlighted the pivotal role of these forces in regulating cellular plasticity during endothelial-to-hematopoietic transition (EHT) and endothelial-to-mesenchymal transition (EndMT), two processes essential for embryogenesis, tissue repair, and disease progression. EHT contributes to hematopoietic stem cell formation, and EndMT to valve formation and vessel sprouting. When misregulated, both processes cause vascular pathologies such as fibrosis, cancer metastasis, and atherosclerosis. This review provides an overview of how biomechanical cues influence EC fate decisions and behavioral transitions. We explore how external biomechanical forces are sensed at the endothelial cell surface, transmitted through intracellular adaptors, and affect changes at the transcriptional level. Understanding these mechanotransduction pathways during cell fate transition not only deepens our knowledge of endothelial cell plasticity but also provides insight into potential root causes of and treatments for vascular diseases.

Keywords:  Biomechanical forces; Endothelial-to-hematopoietic transition; Endothelial-to-mesenchymal transition; Vascular development

DOI:  https://doi.org/10.1016/j.semcdb.2025.103623
Biochem Soc Trans. 2025 Jul 04. pii: BST20253059. [Epub ahead of print]

Molecular insight on the role of the phosphoinositide PIP3 in regulating the protein kinases Akt, PDK1, and BTK.

Alexandria L Shaw, John E Burke.

  Protein kinases are master regulators of myriad processes in eukaryotic cells playing critical roles in growth, metabolism, cellular differentiation, and motility. A subclass of protein kinases is regulated by their ability to be localized and activated by the phosphoinositide phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This includes multiple members of the AGC and TEC family kinases, which contain PIP3 binding pleckstrin homology (PH) domains. It has been postulated that they can be activated by PIP3-mediated disruption of autoinhibitory interactions between their kinase domains and PH domains. There has been considerable controversy based on differing molecular models for how these kinases are regulated by lipid binding and post-translational modifications. This review focuses on understanding the molecular underpinnings for how the PH domains of these enzymes regulate kinase activity and what role PIP3 plays in pathway activation. A specific focus is on the integration of experimental data derived from X-ray crystallography, cryo-electron microscopy, and hydrogen deuterium exchange mass spectrometry along with recent advances in artifical intelligence enabled protein modeling. The main lipid-binding enzymes described are the AGC protein kinases 3-phosphoinositide-dependent kinase (PDK1) and Akt, and the TEC family kinase, Bruton's agammaglobulinemia tyrosine kinase (BTK).

Keywords:  PDK1; cryo-electron microscopy; hydrogen-deuterium exchange mass spectrometry; kinases; proto-oncogene proteins c-akt; structural biology

DOI:  https://doi.org/10.1042/BST20253059
Br J Cancer. 2025 Jul 04.

AKT/mTOR as a targetable hub to overcome multimodal resistance to EGFR inhibitors in oesophageal squamous cell carcinoma.

Lindsay C Spender, Dale M Watt, Mark A Baxter, Morven K Shuttleworth, Kateah Walker, Alice R Savage, Hollie A Clements, Yury Kapelyukh, Susan E Bray, Sharon I King, C Roland Wolf, Gareth J Inman, Shaun V Walsh, Karen Blyth, Russell D Petty.

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is associated with late-stage diagnosis, limited treatment options, the development of drug resistance and poor outcome. Epidermal growth factor receptor is frequently dysregulated in ESCC. EGFR copy number gain and/or protein overexpression are beneficial as predictive biomarkers for EGFR inhibitor therapy; however, inherent and acquired resistance limit response rates, and durable disease control is infrequent.
METHODS: This study investigates the causes of resistance to the off-patent EGFR inhibitor gefitinib in three gefitinib-resistance model systems: intrinsic, acquired resistance and growth factor (TGFβ)-induced resistance. Findings from studies in 13 ESCC cell lines were validated in tumour specimens from the GO2 clinical trial (n = 32), publicly available ESCC datasets (n = 264), cell line-derived xenograft (CDX) and patient-derived organoid (PDO) model systems.
RESULTS: Gefitinib resistance in ESCC was associated with diverse mechanisms, including RTK signalling via PDGFRβ and IGFBP3/IGF1/IGF1R, as well as EMT, but was consistently associated with the maintenance of signalling via AKT across multiple cell lines and model systems. AKT or mTOR inhibitors synergised with gefitinib in 2D and anchorage-independent 3D assays. Gefitinib plus the AKT inhibitor capivasertib (Truqap™) was efficacious in human CDX and PDO models.
DISCUSSION: Combining AKT/mTOR inhibitors with EGFR inhibitors in EGFR-driven ESCC shows synergism but with elevated toxicity. Monotherapy AKT/mTOR inhibitors or combined therapy at reduced doses could offer improved, cost-effective therapy options for gefitinib-resistant cancer.

DOI: https://doi.org/10.1038/s41416-025-03093-3
Nat Commun. 2025 Jul 01. 16(1): 5902

Generation of mature epicardium derived from human-induced pluripotent stem cells via inhibition of mTOR signaling.

Yu Tian, Antonio Lucena-Cacace, Kanae Tani, Amanda Putri Elvandari, Rodolfo S Allendes Osorio, Megumi Narita, Yasuko Matsumura, Ian Costa Paixao, Yutaro Miyoshi, Azusa Inagaki, Julia Junghof, Yoshinori Yoshida.

Reactivating the human epicardium post-cardiac injury holds promise for cardiac tissue regeneration. Despite successful differentiation protocols yielding pure, self-renewing epicardial cells from induced pluripotent stem cells (iPSCs), these cells maintain an embryonic, proliferative state, impeding adult epicardial reactivation investigation. We introduce an optimized method that employs mammalian target of rapamycin (mTOR) signaling inhibition in embryonic epicardium, inducing a quiescent state that enhances multi-step epicardial maturation. This yields functionally mature epicardium, valuable for modeling adult epicardial reactivation. Furthermore, we assess cardiac organoids with cardiomyocytes and mature epicardium, probing molecular mechanisms governing epicardial quiescence during cardiac maturation. Our results highlight iPSC-derived mature epicardium's potential in investigating adult epicardial reactivation, pivotal for effective cardiac regeneration. Additionally, the cardiac organoid model offers insight into intricate cardiomyocyte-epicardium interactions in cardiac development and regeneration.

DOI: https://doi.org/10.1038/s41467-025-60934-8
Nature. 2025 Jul;643(8070): 47-59

The Somatic Mosaicism across Human Tissues Network.

Somatic Mosaicism across Human Tissues Network

From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.

DOI: https://doi.org/10.1038/s41586-025-09096-7
Nat Commun. 2025 Jul 01. 16(1): 5818

PI3Kγ signaling controls trafficking of CD8+ T cells between lymphoid and non-lymphoid organs and drives hypertension in a murine model.

Marialuisa Perrotta, Sara Perrotta, Lorenzo Carnevale, Agnese Migliaccio, Fabio Pallante, Ryszard Nosalski, Tomasz J Guzik, Stefania Fardella, Emilio Hirsch, Valentina Fardella, Azzurra Zonfrilli, Jacopo Pacella, Matthias P Wymann, Giuseppe Lembo, Daniela Carnevale.

Activated immune cells infiltrate the vasculature during the pathophysiology of hypertension by establishing a vascular-immune interface that contributes to blood pressure dysregulation and organ failure. Many observations indicate a key role of CD8+ T cells in hypertension but mechanisms regulating their activation and interplay with the cardiovascular system are still unknown. In murine model, here we show that a specific member of the phosphoinositide-3-kinases (PI3K) family of lipid kinases, PI3Kγ, is a key intracellular signaling of CD8+ T cells activation and RANTES/CCL5 secretion in hypertension: CCL5-CCR5 signaling is crucial for the establishment of the vascular-immune interface in peripheral organs, lastly contributing to CD8+ tissue infiltration, organ dysfunction and blood pressure elevation. Our studies identify PI3Kγ as a booster of effector CD8+ T cell function, even in the absence of external stimuli. Lastly, an enhanced PI3Kγ signaling mediates the bystander activation of CD8+ T cells and proves effective in transferring the hypertensive phenotype between mice.

DOI: https://doi.org/10.1038/s41467-025-61009-4